Abatacept (ORENCIA) for Rheumatoid Arthritis

1
Abatacept (ORENCIA) for Rheumatoid Arthritis

• Biological License Application
• Arthritis Advisory Committee
• September 6, 2005

2
Abatacept

• Proposed indications for abatacept
• For use in adult patients with moderately to
  severely active rheumatoid arthritis who have had
  an inadequate response to one or more biologic or
  non-biologic DMARDs
• Reducing signs and symptoms
• Inducing major clinical response
• Inhibiting the progression of structural damage
• Improving physical function
• Abatacept may be used as monotherapy or
  concomitantly with methotrexate or other
  non-biologic DMARD therapy

3
Overview of FDA Presentation

• Clinical Development Program and Study Design
• Efficacy Data
• Improvement of Signs and Symptoms
• Improvement of Physical Function
• Inhibition of Radiographic Progression
• Safety Data
• Summary

4
Abatacept BLA

• CLINICAL DEVELOPMENT PROGRAM
• STUDY DESIGN

5
Abatacept Clinical TrialsRandomized,
Double-Blind, Placebo-Controlled
6
Study Design-Common Features

• Randomized, double-blind, placebo-controlled
  studies
• Major Inclusion Criteria
• Diagnosis of RA (1987 ARA criteria)
• Active disease despite DMARD therapy at
  randomization
• 10 swollen joints (66 joint count)
• 12 tender joints (68 joint count)
• CRP 1 mg/dL
• Stable doses of prednisone and NSAIDs allowed
• Abatacept Dosing Week 0, 2, and 4, then Q4 weeks
  
• Weight-based dosing
• Weight-Tiered-based dosing
• lt60kg Abatacept 500 mg IV
• 60 kg to 100 kg Abatacept 750 mg IV
• gt 100 kg Abatacept 1000 mg IV

7
Study Design-Common Features

• Statistical Analyses
• Modified ITT efficacy analyses performed for all
  trials
• Sequential testing for co-primary endpoints
• Co-primary endpoint tested for significance only
  if preceding co-primary endpoint was
  statistically significant
• Type I error rate of 5 maintained
• Adjustment for multiple doses performed using
  global testing then pairwise comparisons for
  individual doses

8
Study Design-Common Features

• Statistical Analyses
• ACR and Health Assessment Questionnaire (HAQ)
  response rates
• Categorical Endpoints
• Chi-square Test
• Non-responder imputation for missing data
• Radiographic Progression
• Genant-modified Sharp Score
• Rank-based nonparametric ANCOVA model
• Linear extrapolation for missing data

9
Study IM101-102 Concomitant MTX Study

• 12 month study
• Active RA despite MTX therapy
• 656 patients randomized 21
• Weight-Tiered-dose Abatacept MTX (n433)
• Placebo MTX (n219)
• Sequential Co-Primary Endpoints
• ACR 20 response at 6 months
• Improvement in Physical Function (HAQ) at 12
  months
• Inhibition of Radiographic Progression at 12
  months

10
Study IM101-100 Dose-Ranging Study

• 12 month Study
• Active RA despite MTX therapy
• 339 patients randomized 111
• Abatacept 10 mg/kg MTX (n115)
• Abatacept 2 mg/kg MTX (n105)
• Placebo MTX (n119)
• Primary Endpoint
• ACR 20 response at 6 months

11
Study IM101-029 TNF-Blocker Failure Study

• 6 month Study
• Active RA despite TNF-blocker therapy DMARD
• Etanercept or Infliximab
• Following drug-washout 393 patients with active
  RA randomized 21
• Weight-Tiered-dose Abatacept DMARD (n258)
• Placebo DMARD (n133)
• Co-Primary Endpoints
• ACR 20 response at 6 months
• Improvement in Physical Function (HAQ) at 6 months

12
Study IM101-031 Clinical Practice Study

• 12 month Study
• Active RA despite DMARD therapy
• non-biologic and/or biologic DMARDs
• Patients with co-morbid conditions permitted
• 1441 patients randomized 21
• Baseline therapy Weight-tiered dose Abatacept
  (n959)
• Baseline therapy Placebo (n482)
• Primary Objective
• Safety
• Exploratory Endpoint
• Improvement in Physical Function (HAQ) at Day 365

13
Clinical Studies-Study Conduct

• Baseline Patient Demographics (mean)
• 52 years of age
• 79 Female
• 85 White and 4 Black
• Baseline Disease Activity (mean)
• 10 years RA duration
• 21 swollen joints
• 31 tender joints
• 79 RF()
• MTX 16 mg Qweek

14
Abatacept BLA

• EFFICACY ANALYSES
• Signs and Symptoms

15
IM101-102 Concomitant MTX Study Signs
Symptoms ACR Responses
plt0.001
16
IM101-102 Concomitant MTX Study Signs
Symptoms ACR 20 Response Time Course
17
IM101-102 Concomitant MTX Study Signs
Symptoms Major Clinical Response
18
IM101-102 Concomitant MTX Study Median
Improvement in ACR Components at Day 169
19
IM101-102 Concomitant MTX StudyDAS28 Response
at Day 365
plt0.001
20
IM101-100 Dose-Ranging Study Signs Symptoms
ACR Responses
p0.03
21
IM101-029 TNF-Blocker Failure Study Signs
Symptoms ACR Responses at Day 169
p0.003
22
IM101-029 TNF-Blocker Failure Study Signs
Symptoms DAS28 Response at Day 169
plt0.001
23
Exploratory AnalysisCriteria to Assess Very Low
Disease Activity

• EULAR-definition of remission is defined as a
  DAS28lt2.6
• However, patients with a EULAR definition of
  remission can still have several swollen or
  tender joints
• Alternative criterion for very low disease
  activity DAS28lt2.6 AND 1 swollen and 1 tender
  joint

24
Criteria to Assess Very Low Disease Activity
IM101-102 Concomitant MTX Study
25
Criteria to Assess Very Low Disease Activity
IM101-029 TNF-Blocker Failure Study
26
Exploratory AnalysisWeight-Tiered-Dosing ACR20
Responders
27
Abatacept BLA

• EFFICACY ANALYSES
• Improvement in Physical Function

28
IM101-102 Concomitant MTX Study Improvement in
HAQ score 0.3u at Day 365
29
IM101-100 Dose-Ranging Study Improvement in HAQ
score 0.3u at Day 360
30
IM101-100 Dose-Ranging Study Improvement in HAQ
score 0.3u Open-Label Study
31
Abatacept BLA

• EFFICACY ANALYSES
• Inhibition of Radiographic Progression

32
IM101-102 Concomitant MTX Study Mean Change In
Genant-Modified Sharp Scores at Day 365
33
IM101-102 Concomitant MTX Study Mean Change in
Genant-Modified Sharp Score Components
34
Study IM103-002 Monotherapy Study

• 3 month study
• Active RA despite DMARD therapy
• 112 patients randomized
• Abatacept (n90)
• 0.5 mg/kg (n26), 2 mg/kg (n32), or 10 mg/kg
  (n32)
• Placebo (n32)
• Primary Endpoint
• ACR 20 response at Day 85

35
Study IM103-002 Monotherapy Study ACR Responses
at Day 85
36
AbataceptEfficacy Analysis

• Subset Analyses by
• Baseline Demographics
• Age
• Sex
• Race
• Weight
• Baseline Disease Activity
• Disease Duration
• Swollen Tender Joints
• CRP
• Genant-modified Sharp Score
• HAQ

37
Abatacept BLA

• SAFETY ANALYSES

38
Safety Analyses Overview

• Safety Assessment Based on 5 Studies
• IM101100, IM101101, IM101102, IM101029, IM101031
• Double-Blind Periods
• 1955 Abatacept-treated patients (1688
  person-years)
• 989 Placebo-treated patients (795 person-years)
• Open-Label Periods Double-Blind Periods
• 2688 Abatacept-treated patients

39
Cumulative Extent of Exposure
40
Deaths

• 26 total deaths
• 16 patients died during the double-blind periods
• 10 (0.5) abatacept-treated patients
• 4 died from cardiovascular disorders
• 3 found dead at home
• 2 died from malignancies
• 1 died from infection
• 6 (0.6) placebo-treated patients
• 2 died from cardiovascular disorders
• 1 found dead at home
• 1 died from malignancy
• 2 died from infection

41
Deaths

• Analysis of the individual deaths did not suggest
  a safety signal for any single type of AE
• 8 of the deaths in the Abatacept group occurred
  during a study that permitted enrollment of
  patients with co-morbidities

42
Serious Adverse Events

• 14 of Abatacept-treated patients had an SAE
  compared to 12 placebo-treated patients
• 3 of Abatacept-treated patients had an
  infectious SAE compared to 2 placebo-treated
  patients

43
Malignancies Double-Blind Periods
44
Solid Organ TumorsAbatacept-Treated
Patients-Double Blind Periods
45
Malignancies Open-Label Periods

• 47 patients developed 52 neoplasms
• 26 malignancies
• 13 solid-organ tumors
• 4 lung cancers
• 2 ovarian cancers
• 2 endometrial cancers
• 1 case each of breast, prostate, melanoma,
  cervical, and rectal cancer
• 3 lymphomas

46
Most Frequently Observed vs. Expected Malignancies
47
Incidence Rates of Malignancies
48
Malignancies

• 3 potentially concerning malignancies
• Lung Cancer
• 8 cases of lung cancer in patients receiving
  abatacept
• Breast Cancer and Lymphoma
• Pre-clinical studies demonstrated increased rate
  of mammary tumors and lymphomas in mice that was
  believed to be secondary to abatacept-induced
  chronic immunosuppression and MMTV and MLV
• Immunosuppression and RA both associated with
  increased risk of lymphoma

49
Lung Cancer Incidence
50
Breast Cancer Lymphoma

• Breast Cancer
• 3 (0.1) cases of breast cancer reported in
  abatacept-treated patients compared to 2 (0.2)
  cases reported in placebo-treated patients
• Current evidence does not suggest abatacept
  increases the rate of breast cancer
• Lymphoma
• 4 cases of lymphoma reported in patients
  receiving abatacept
• Approximately 4-fold higher than general US
  population
• However, increased rate of lymphoma in RA
  patients, particularly those with high disease
  activity

51
Serious Infections
52
Infections of Special Interest
53
AEs in Abatacept w/ Biologic RA Therapy

• A total of 204 patients received abatacept and
  concomitant biologic RA therapy during the
  double-blind period representing 173 person-years
  of exposure
• Majority of patients were from studies IM101-101
  (n85) and IM101-031 (n103)
• gt90 TNF-blocker therapy
• Study IM101-101 compared the combination of
  abatacept 2 mg/kg etanercept to placebo
  etanercept

54
AEs in Abatacept w/ Biologic RA Therapy
55
SAEs with Abatacept Concomitant RA
TherapyStudy IM101031
56
Infusion Reactions

• Infusion Reactions within 1 hour post-infusion
• 9 of abatacept-treated patients vs. 6
  placebo-treated patients
• Infusion Reactions within 24 hours post-infusion
• 23 of abatacept-treated patients vs. 19
  placebo-treated patients
• 2 cases of anaphylactic reactions in patients
  receiving abatacept

57
Immunogenicity Clinical Laboratory Values

• Immunogenicity of Abatacept
• Overall, 1.6 of patients treated with abatacept
  developed antibodies to abatacept
• 5.8 of abatacept patients who had discontinued
  therapy for at least 56 days developed antibodies
  to abatacept
• Changes in Clinical Laboratory Values
• no clinically meaningful differences between
  patients treated with abatacept compared to
  placebo regarding blood chemistry and hematologic
  laboratory values

58
Autoimmune Symptoms Disorders

• 3 of Abatacept-treated patients reported
  autoimmune-related AEs compared to 2 of
  placebo-treated patients during the Double-Blind
  period
• Most common symptoms were associated with RA
• e.g., Keratoconjunctivitis sicca, Sjogrens
  syndrome
• Psoriasis was more frequent in patients treated
  with abatacept compared to placebo (0.5 vs.
  0.1)

59
Autoimmune Symptoms Disorders ANA and ds-DNA
Antibody Formation at 12 months
60
AEs in patients with Co-MorbiditiesStudy IM101031

• Study IM101-031 permitted patients with
  co-morbidities including COPD, diabetes, asthma,
  and CHF
• Diabetes, asthma, or CHF no apparent increase in
  AEs or SAEs
• COPD AEs reported in 97 of abatacept-treated
  patients vs. 88 of placebo-treated patients
• Respiratory AEs more common with abatacept (43
  vs. 24)
• SAEs more common with (27 vs. 6)
• No reported deaths

61
Summary

• The studies presented here show
  abatacept-treatment associated differences
  regarding
• improvement in signs and symptoms
• improvement of physical function
• Inhibition of radiographic progression
• There was a higher rate of serious infections in
  patients treated with abatacept, especially with
  patients receiving concomitant TNF-blocking
  agents
• Overall malignancy rates were not substantially
  different between abatacept (1.5) and placebo
  (1.1) treated patients
• However, abatacept treated patients had more
  cases of lung cancer and the rate of lymphomas
  was higher than expected compared to the general
  US population

62
Summary

• Infusion-related reactions were observed
  including hypersensitivity reactions and 2 cases
  of anaphylaxis
• Patients with COPD treated with abatacept had a
  higher incidence of adverse events and serious
  adverse events, particularly respiratory
  disorders